Three Part Question

Clinical Scenario

You have always used blood cardioplegia but you start to work for a consultant who uses crystalloid cardioplegia. He evangelically states that crystalloid is cheaper, quicker and gives you a better view when performing distal coronary artery anastomoses. You have always been told that blood is superior as it is a more physiological buffer and has an important oxygen carrying capacity. You then realise that you have never actually read a single paper on the comparison between these two solutions even though you use it every day and resolve to look up the evidence.

Search Strategy

Medline 1950Feb 2008 using the OVID interface.
[blood.mp] AND [crystalloid.mp] AND [cardioplegia.mp OR cardioplegic.mp OR exp cardioplegic solutions/].

Search Outcome

Medline found 501 abstracts. We chose to exclude RCTs with fewer than 50 patients and selected 22 papers as representing the best evidence on this topic.

The LOS and CK-MB data suffered due to the lack of data from the two largest studies that had 1000 and 1400 patients in. Thus only 10 trials available for the LOS data and 7 for CK-MB.

The lack of the Ovrum study in the low output syndrome category is curious as Ovrum collected data on IABP use and inotrope use and Guru successfully contacted Ovrum for their study, but clearly did not ask for these data which presumably would all have been available

The other large study by Martin also presented IABP use, MI and inotrope use, although they did not respond to Guru et al.

The confounding factor is that the benefit in neurological outcome is likely to have been from the systemic hypothermia rather than the cardioplegic solution, and there were no non-neurologically difference outcomes

The following discussion implies that this study had to be stopped early due to the adverse neurological event rate although this is not mentioned in the paper

Comment(s)

Prof Fremes' Toronto group in 2006 performed a meta-analysis of 34 randomised controlled trials. Most were small and there were only two with more than 1000 patients in total and another three with more than 100 patients in the blood cardioplegia arm. In total there were 5000 patients included in these studies (but half were from two studies). They reported that the incidence of low output syndrome (LOS) was significantly lower with blood cardioplegia (BCP) with an odds ratio of 0.54 (95% CI 0.340.84) and the CK-MB release was higher by a weighted mean difference of 5.7 U/l with crystalloid cardioplegia (CCP) at 24 h (95% CI 1.610.2). There was no difference in the aggregated MI or mortality rates. However, there are significant weaknesses to these findings as the authors were unable to obtain any data on low output syndrome or CK-MB from the two studies containing more than 1000 patients, despite successfully contacting Ovrum's group which did collect some of this data [Ovrum, Martin]. Thus, the LOS aggregate finding was based on only 10 of the 34 trials (879 patients), and the CK-MB findings came from only seven trials. Furthermore, while CK-MB at 24 h appears in their abstract as a significant finding, in their full paper they report that there is no clinically significant difference at 1 h or 48 h post-operatively in CK-MB. Additionally, cold blood cardioplegia and warm blood cardioplegia studies are combined with a range of systemic temperatures.

The largest prospective randomised controlled trial (PRCT) was by Ovrum et al. in 2004. Two surgeons performed 1440 CABG procedures randomised to either cold CCP or cold BCP. The clinical course, systemic temperature and delivery methods were unified for all patients and emergencies, redos and low EF patients were included. No differences were seen for perioperative myocardial infarction, or mortality. Additionally, in subgroups of patients at higher operative risk (female sex, age >70 years, unstable angina, diabetes, emergency operation, ejection fraction <0.50, crossclamping time >50 min, and EuroSCORE >4) were identical.

The other large trial was conducted by Martin et al. from 19901992. One thousand-and-one patients undergoing elective CABG were randomised to either (1) systemic hypothermia at 28° and intermittent 25 mEq/l potassium cold crystalloid cardioplegia or (2) antegrade high potassium (20 mEq/l) warm blood cardioplegia followed by continuous retrograde low potassium (19 mEq/l) warm blood cardioplegia. There was an unexpectedly high rate of perioperative strokes, delayed stroke and total neurologic events, which caused the study to be stopped early. At this stage there were no differences in mortality, IABP use, inotrope use, or hospital stay. When considering the blood vs. crystalloid debate, this paper confounds the issue, as despite its large size, both the equivalent myocardial outcomes and adverse neurological outcomes may be explained in terms of temperature rather than cardioplegic solution.

No other RCTs come near these two in terms of numbers, and only three have more than 100 patients in the blood cardioplegia group. Iverson et al. in 1984 reported slight but significant improvements in left ventricular stroke work index and creatinine kinase levels in an RCT of 207 patients, Lajos et al. compared three groups, warm BCP, cold BCP and cold CCP in 163 patients. There were no differences between the cold BCP and cold CCP groups but the warm heart consumed three times the myocardial oxygen of the cold heart and 3 of 4 strokes occurred in the warm BCP group. Jacquet et al. compared intermittent warm cardioplegia with antegrade and retrograde cold cardioplegia with systemic hypothermia in 200 patients. There were no differences in death, stroke, inotrope use or IABP but ventricular fibrillation after cross-clamp release was more common with crystalloid and more vasoconstrictors were needed on bypass with systemic normothermia and blood cardioplegia.

We selected a further 15 RCTs reporting over 50 patients (summarised in the Table). Of these, eight reported statistically significant clinical outcomes in favour of blood cardioplegia and five reported statistically significant differences in enzyme release in favour of blood cardioplegia. No studies reported findings in favour of crystalloid cardioplegia other than outcomes such as vasoconstrictor use on bypass and myocardial oxygen uptake during bypass, which occurred when cold crystalloid was compared to warm blood cardioplegia.
Thus, the literature is far from conclusive. This is reflected in a survey of practice in the UK from 2004 which found that of the surgeons performing on-pump CABG, 56% use cold blood cardioplegia, 14% use warm blood cardioplegia, 14% use crystalloid cardioplegia, 21% use retrograde infusion and 16% do not use any cardioplegia, preferring cross-clamp fibrillation!

Clinical Bottom Line

The meta-analysis of 34 randomised trials by Prof Fremes (2006) found a significantly lower incidence of low output syndrome (LOS) and CK-MB release with blood cardioplegia. He found no differences in myocardial infarction or mortality. Ovrum (2006) randomised 1440 patients to antegrade cold blood or crystalloid and found no clinical differences, and the second paper by Martin (1994) of 1001 patients compared warm blood to cold crystalloid but the study had to be stopped due to a high incidence of neurological events in the warm blood group. We reviewed a further 18 randomised trials reporting over 50 patients. Of these, 10 reported some statistically significant clinical outcomes in favour of blood cardioplegia and five reported statistically significant differences in enzyme release in favour of blood cardioplegia.